1-(beta-phenyl-hydroxyethyl)-2-imino-1, 2-dihydropyridine and hydrochloride



3,040,050 1C Patented June 19, 1962 resented as follows in whichZ-aminopyridine is the 3,040,050 specific 2-amino heterocyclic compound:

1-(BETA-PHENYL-HYDROXYETHYL)-2-IMINO-1,2- DIHYDROPYRIDINE ANDHYDROCHLORIDE John H. Biel, Milwaukee, Wis., assignor to Lakeside 5 OHLaboratories, Inc., Milwaukee, Wis., a corporation of gehgare F1] M 1 6S 1 7 o rawing. ed ar. 19 0, er. No. 1 ,979 CHPCHflS 2 Claims. or.260-296) \N NH:

This invention relates to novel chemical compounds 10 and processes ofproducing the same. More particularly, this invention is concerned withnovel heterocyclic N phenethanolamines, processes of producing the sameand 5 uses therefor.

According to the present invention there are provided novel heterocyclicphenethanolamines of the formulae 11 wherein is the phenyl group. Thereaction shows the possible formation of two tautomeric isomers. This isbecause 2-amin0pyridine exists in tautomeric equilibrium as follows:

1- (beta-phenyl-beta-hydroxyethyl) -2-lmin0-1,2-d1hy dropyridine NH (2)NH 13. 1TH 1 CHaCH- H N 5H (Imino tautomer)1-(beta-pheuylbeta-hydroxyethyl)-2-lmlno-1,2-dihydroq e y the reactmtspyrimidine 3o pyr m dine, Z-ammopyrazrne, Z-ammooxazolme and 2-ammomndazohne also exist as equilibrium mixtures of 0. NH suchtautomeric :forms and thus could lead to isomeric A reaction productscomparable to those for Z-aminopyridine N N-CH2CH shown in Formulas Iand II above. However, under l the reaction conditions describedhereinafter the imino structure is favored and is supported by analogywith 1'(beta'phenyl'beta'hydroxygthyl)'2'lmmo'lz'dlhydm' the reaction ofethylene oxide and Z-aminopyridine.

Ber. 68B, 397 1935 'C.A. 29, 3339 1935 D OH 7 The reaction between the2-amino heterocyclic com- 40 pound and styrene oxide can be effected bybringing the reactants into intimate contact with each other in asuitable liquid reaction medium. A lower alcohol such as NE methanol orethanol can be used for the reaction medium. The reaction proceeds atroom temperature and 2'1m1m'3- 'gigzfiig can be terminated with theproduction of acceptable yields in about three to six hours. Longertimes can be used, E if desired, to bring the reaction to greatercompletion.

' --N-CH:CH An alkali metal amide such as lithium amide or sod- 5 amidecan be used in a small amount to catalyze the NH 5O reaction but withsuch agents an anhydrous reaction 0 medium such as toluene or ethyleneglycol dimethyl1-(beta-phenyl-beta-hydroxyethyl)-3'(z-imino'2i3'dihydrm' ether must beused. Under such conditions the reaction also proceeds at roomtemperature but elevated temperatures such as the reflux temperature canbe used to increase the reaction rate if desired.

N l Q The desired product is readily separated from the re- NH OH actionmixture by conventional means. N Acid addition salts of the novelcompounds of this 2-imino-3-(beta-phenyl-beta-hydroxyethyl)-2,3-dlhydroinvention are produced bycontacting them with a suitimidazole able acid such as a mineral acidhke sulfurlc acid or hydrochloric acid, or an organic acid such asformic and nontoxic acid addition salts thereof. acid, Citric acid,fllmafic acid malei? acid- The compounds provided by this invention canbe pro- The described compounds, advisably m the form of duced byreacting the appropriate Z-amino heterocyclic nontoxic acid additionsalts, exert central nervous sys compound with styrene oxide. Thisreaction can be reptern stimulating action in animals and humans buthave a negligible effect on the cardiovascular system. In addition, thecompounds have analgetic and muscle relaxant activity. The compoundsalso sensitize animals to epinephrine, which is a property exhibited bythe antidepressant Tofranil. The oral route of administration isrecommended.

The compounds, advisably in the form of a nontoxic acid addition salt,can be administered to animals and humans as pure compounds. However, inorder to obtain a more satisfactory volume to dosage relationship, thecompounds are generally formulated with a suitable pharmaceuticalcarrier such as starch, sugar, talc or water. The compositions then canbe converted into suitable unit-dosage forms such as tablets andcapsules. A dosage of 50 to 300 mgm. per day is usually a satisfactorytotal dosage so that the unit-dosage forms can be formulated containinggradient amounts of the active agent so that spaced administrationthroughout the day will give the total administration desired.

A typical tablet can have the composition:

(1) 1 (beta-phenyl-beta-hydroxyethyl)-2-imino-1,2-

dihydropyridine HCl 30 (2) Starch U.S.P. 57 (3) Lactose U.S.P. 73 (4)Talc U.S.P 9 (5) Stearic acid 6 The following examples illustrate thepreparation of some of the compounds of this invention.

EXAMPLE 1 1 -(Beta-Ph enyl-Beta-H ydroxyethyl -2-I m inc-1 ,2-Dihydropyridirze A mixture containing 18.8 g. (0.20 mole) of2-aminopyridine, 0.55 g. of lithium amide and 75 cc. of anhydroustoluene was refluxed for 1.5 hours. Styrene oxide (12.0 g.=0.10 mole)was then added to the reaction mixture with stirring over a period often minutes. The reaction mixture was stirred and refluxed for anadditional 3.5 hours. A crystalline precipitate was formed during thereaction which was removed by filtration, M.P. 170-171 C., 1.5 g. Thefiltrate was concentrated to dryness and a dark residue remained whichwas crystallized from anhydrous ether; yield 6.0 g. Uponrecrystallization of the crude solid from 30 cc. of isopropyl alcohol,2.0 g. of a light yellow solid was isolated; M.P. 170-171 C.

EXAMPLE 2 1-(Beta-Phenyl-BetmHydroxyethyl) -2-Imin0-1 ,2-Dihydropyridine Hydrochloride Two grams of the product of Example 1(M.P. 170- 171 C.) was dissolved in isopropyl alcohol and converted tothe hydrochloride salt by neutralization with ethereal hydrochloricacid, yield 2.2 g. (93%), M.P. 199-200 C.

Anal.-Calcd. for C; H ClN O: Cl, 14.17. Found: Cl, 4,18, l 4 n i 4EXAMPLE 3 J -(Beta-Phenyl-Beta-Hydroxyethyl) -Z-lmin0-1 ,2-Dihydropyridine This compound was also obtained by allowing an ethanolsolution of 24.0 g. (0.20 mole) of styrene oxide and 17.1 g. (0.18 mole)Z-aminopyn'dine to stand at room temperature for four days. The yield ofyellow, crystalline product was 9.0 g. (23%), M.P. 168-170 C. Thehydrochloride salt melted at ZOO-201 C.

EXAMPLE 4 2-Imin -3- (Beta-Ph enyl-Beta-Hydroxyethyl) -2,3-Dihydrothiazole An ethanol solution containing 18 g. (0.18 mole) of 2-aminothiazole and 24 g. (0.20 mole) of styrene oxide was allowed tostand at room temperature for 4 days; 9.3 g. (24%) of a light greyprecipitate was collected, M.P. 159-160 C., which on recrystallizationfrom isopropyl alcohol (3 g. in cc.) melted at 167-168 C.

EXAMPLE 5 2 Imin0-3-(Beta-Pkenyl-Beta-Hydroxyethyl) -2,3

Dihydroth iazole H ydroch loride Six g. (0.027 mole) of therecrystallized base from Example 4 was dissolved in 200 cc. of isopropylalcohol and neutralized With 22 cc. of 2.36 N ethereal hydrochloricacid, yield 6.4 g. (92% M.P. 208209 C.

Anal.Calcd. for C H CIN OS: Cl-, 13.84. Found: Cl-, 13.84.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. 1-( beta-phenyl-tbeta-hydroxyethyl) 2 imino 1,2- dihydropyridine.

2. 1-(beta-phenyl-beta-hydroxyethyl) 2 imino 1,2- dihydropyridinehydrochloride.

References Cited in the file of this patent UNITED STATES PATENTSZiegenbein et al.: Chem. Ber., vol. 90, pages 2291-2301 1957).

1. 1-(BETA-PHENY-BETA-HYDROXYETHYL)-2IMINO-1.2 DIHYDROPYRIDINE.